Regulation of hepatic gluconeogenesis by hormones such as glucagon, insulin, epinephrine, vasopressin and angiotensin is well established. In contrast, however, relatively few studies have examined the effects of these hormones, on regulation of the various processes involved in energy generation in the liver and heart. It may be expected that stimulation of gluconeogenesis from 3-carbon precursors (eg. pyruvate and lactate) by glucagon or alpha-adrenergic agonist, phenylephrine, would decrease the oxidation of these compounds. However, preliminary data indicate that the alpha-adrenergic agonist, phenylephrine, increases the oxidation of (2-14C) pyruvate both in the perfused rat liver and the perfused working heart preparation, demonstrating that the metabolic flux through the tricarboxylic acid cycle (TCA cycle) is stimulated by alpha-adrenergic stimulation. Therefore, it is the overall objective of this proposal to characterize and elucidate the effect of epinephrine, vasopressin, angiotensin, glucagon and insulin on the key regulatory processes involved in carbohydrate energy metabolism. Initially studies will be performed to elucidate the effects of the various hormones described above on the metabolic flux through the pyruvate dehydrogenase (PDH) complex and the TCA cycle. These and additional studies with (2-14C) labeled acetate will indicate whether the increased TCA cycle activity, during for eg. alpha-adrenergic stimulation of livers and hearts, is a function of increased pyruvate carboxylation or increased metabolic flux through the PDH reaction. Secondly, employing (1-14C) monomethyl alpha-ketoglutarate, as a source of intracellular alpha-ketoglutarate, studies will be performed to investigate the effects of the various hormones on the activity of one of the key regulatory enzymes of the TCA cycle, the alpha-ketoglutarate dehydrogenase complex in intact perfused rat livers and hearts. Employing this approach to overcome cellular impermeability to free alpha-ketoglutarate, this will be the initial attempt, thus far, to elucidate directly the regulation of the alpha-ketoglutarate dehydrogenase complex in an intact perfused organ preparation. Studies in working heart preparations will also investigate the relationship between energy requirements of the tissue (due to alterations in afterload) and activity of the TCA cycle and the alpha-ketoglutarate dehydrogenase complex. This latter approach will also demonstrate if hormone (eg. epinephrine) elicited metabolic alterations are secondary to the inotropic effects of the hormones.
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